Abstract
How stem cells and progenitors balance between self-renewal and differentiation is a central issue of stem cell biology. Here, we describe a novel and essential function of Drosophila Fzr/Cdh1, an evolutionary conserved protein, during the differentiation of neural stem cell (NSC) lineages in the central nervous system. We show that Fzr, a known co-activator of Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase, promotes the production of neurons from neural progenitors called ganglion mother cells (GMCs). However, knockdown of APC/C subunit Ida or another APC/C co-activator CDC20 does not similarly impair GMC-neuron transition. We also observe a concomitant loss of differentiation factor Prospero expression and ectopic accumulation of mitotic kinase Polo in fzr mutant clones, strongly supporting the impairment of GMC to neuron differentiation. Besides functioning in GMCs, Fzr is also present in NSCs to facilitate the production of intermediate neural progenitors from NSCs. Taken together, Fzr plays a novel function in promoting differentiation programs during Drosophila NSC lineage development. Given that human Fzr is inactivated in multiple types of human cancers including brain tumors and that Fzr regulates neurotoxicity in various models of neurodegenerative diseases, our study on the role of Fzr in turning off proliferation in neuronal cells may provide insights into how Fzr deficits may contribute to human neurodegenerative diseases and tumors.
Highlights
Understanding how stem cells maintain their self-renewal capacity and how their progeny differentiate into specific fates are essential to comprehend developmental processes as well as to exploit the therapeutic potential of stem cells for regenerative medicines and cancer treatments
In order to evaluate the possible function of fizzy and cell division cycle related (Fzr) in neural stem cell (NSC) lineage development, we generated mosaic analysis with a repressible cell marker (MARCM) clones for two known mutant alleles of fzr, named fzrA and fzrB, which were isolated by ethyl methanesulfonate (EMS) mutagenesis on X-chromosome (Yamamoto et al, 2014)
The ectopic Ganglion Mother Cell (GMC) phenotype observed in fzr− mutants were fully rescued by expressing an upstream activating sequence (UAS)- Fzr-HA transgene driven by tub-Gal4 from MARCM driver as well as by the insertion of Dp(1;3)DC120, a genomic fragment containing the fzr locus (Figures 1A,B)
Summary
Understanding how stem cells maintain their self-renewal capacity and how their progeny differentiate into specific fates are essential to comprehend developmental processes as well as to exploit the therapeutic potential of stem cells for regenerative medicines and cancer treatments. Erm works together with the SWI/SNF chromatin-remodeling complex Brahma (Brm) in immature INPs to restrain the developmental potential of INPs (Eroglu et al, 2014; Koe et al, 2014; Janssens et al, 2017; Liu et al, 2017) Several studies in both mammals and Drosophila have indicated that neuronal differentiation is actively maintained. Neurons in nerfin-1 mutants first increase their cellular size, switch off neuronal program and start to express the NSC-identity program (Froldi et al, 2015) It remains elusive whether other cellular factors play a role in differentiation of NSC lineages
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